Identification of certain chemokine receptors as fusion/entry co-factors for HIV and the recognition that their ligands function as HIV suppressive factors has substantially extended our understanding of HIV pathogenesis. CCR5, a receptor for the beta chemokines RANTES, MIP-1alpha, and MIP-1beta, serves as a co-receptor for macrophage (M)-tropic HIV, while CXCR4, a receptor for the alpha chemokine SDF-1, is critical for fusion/entry of T cell (T)-tropic HIV. Recent findings that a genetic defect in the CCR5 gene confers resistance to HIV infection has confirmed its significance in HIV pathogenesis. However, in addition to genetic factors affecting expression of these proteins, immunoregulatory mechanisms which can affect the availability of functional co-receptors may influence transmission of either phenotype of HIV, transition from a predominance of one phenotype over the other, and the prognosis of HIV disease. In order to investigate the molecular and cellular mechanisms that control expression of HIV co-receptors and their ligands, we cloned and characterized the promoter regions for the genes encoding these proteins. We demonstrated that RANTES promoter activity is markedly enhanced by stimulation with PMA plus ionomycin, the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta, or CD28 co-stimulation; NF-kappaB/Rel transcriptional factors are responsible for this stimulation. The promoter regions for the HIV co-receptors CXCR4 and CCR5 contain a number of regulatory elements; CCR5 promoter activity is enhanced by IL-2 and downregulated by CD3/CD28 co-stimulation.